US11524969B2ActiveUtilityA1
Pyrrolobenzodiazepines and conjugates thereof as antitumour agents
Est. expiryApr 12, 2038(~11.7 yrs left)· nominal 20-yr term from priority
C07D 519/00A61K 45/06C07D 487/04A61P 35/00A61K 31/5517A61K 47/6803A61K 47/68035
70
PatentIndex Score
1
Cited by
1,064
References
16
Claims
Abstract
A compound with the formula I: (I) and salts and solvates thereof, wherein: R″ is a group of formula II: (II) where each of n and m are independently selected from 1, 2 and 3.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R″ is a group of formula II:
where each of n and m are independently selected from 1, 2 and 3;
R O is selected from the group consisting of H, methyl, ethyl, iso-propyl and benzyl;
Q C is selected from N and CH;
Y and Y′ are selected from O, S, or NH;
when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) C 6-10 carboaryl group or C 5-10 heteroaryl group, wherein said C 6-10 carboaryl or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group, a C 6-10 carboaryl group or a C 5-10 heteroaryl group;
(ib) C 1-5 alkyl;
(ic) C 3-6 cycloalkyl;
wherein each of R 11 , R 12 and R 13 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2 and C3,
R 2 is H or
where R 16a and R 16b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 2′ is selected from the group consisting of:
(iia) C 6-10 carboaryl group or C 5-10 heteroaryl group, wherein said C 6-10 carboaryl or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group, a C 6-10 aryl group or a C 5-10 heteroaryl group;
(iib) C 1-5 alkyl;
(iic) C 3-6 cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2′ group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 2′ is H or
where R 26a and R 26b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from C 1-12 alkyl, C 3-20 heterocyclyl and C 6-20 aryl groups;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 11a is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
and either
(a) R 30 is H, and R 31 is OH, OR A , where R A is C 1-4 alkyl;
(b) R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 30 is H and R 31 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, wherein if R 11a and R 31 are SO z M, M may represent a divalent pharmaceutically acceptable cation
R L is a linker for connection to an antibody Or an antigen-binding fragment of an antibody, which is selected from:
wherein
Q is:
where Q X is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue;
X is:
where a=0 to 5, b=0 to 16, c=0 or 1, d=0 to 5;
G L is a linker for connecting to an antibody or an antigen-binding fragment of an antibody; and
where R L1 and R L2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene or cyclobutylene group;
and e is 0 or 1;
wherein the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the heterocyclyl group in C 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; and
wherein the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S.
2. A compound according to claim 1 , wherein:
a) Y and Y′ are O,
b) R O is H or methyl;
c) R″ is of formula IIa:
where R O1 is selected from the group consisting of H and methyl;
d) R 6 , R 9 , R 6′ and R 9′ are H, and R 7 and R 7′ are methoxy;
e) R 11a is OH;
f) R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound.
3. A compound according to claim 1 of:
(i) formula Ia:
where R 2a and R 2a′ are the same and are selected from:
(ii) formula Ib:
(iii) formula Ic:
wherein R 7a and R 7a′ are the same and are selected from methoxy and benzyloxy.
4. A compound according to claim 2 wherein R L is of formula IIIa, and Q is a dipeptide residue selected from:
CO -Phe-Lys- NH ,
CO -Val-Ala- NH ,
CO -Val-Lys- NH ,
CO -Ala-Lys- NH ,
CO -Val-Cit- NH ,
CO -Phe-Cit- NH ,
CO -Leu-Cit- NH ,
CO -Ile-Cit- NH ,
CO -Phe-Arg- NH , and
CO -Trp-Cit- NH .
5. A compound according to claim 1 , wherein R L is of formula IIIa and, a is 0, c is 1 and d is 2, and b is from 0 to 8.
6. A compound according to claim 1 , wherein R L is of formula IIIa and G L is selected from
(G LL1-1 )
(G LL1-2 )
(G LL2 )
(G LL3-1 )
(G LL3-2 )
(G LL-4 )
(G LL5 )
(G LL6 )
(G LL7 )
(G LL8-1 )
(G LL8-2)
(G LL9-1)
(G LL9-2 )
G L10
G L11
G L12
G L13
where Ar represents phenylene, and X represents C 1-4 alkyl.
7. A compound according to claim 1 , wherein R L is of formula IIIb.
8. A conjugate comprising a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, linked to an antibody or an antigen-binding, fragment of an antibody.
9. A conjugate of formula IV:
L-(D L ) p (IV)
or a pharmaceutically acceptable salt thereof, wherein L is an antibody or an antigen-binding fragment of an antibody, D L is of formula III:
wherein:
R″ is a group of formula II:
where each of n and m are independently selected from 1, 2 and 3;
R O is selected from the group consisting of H, methyl, ethyl, iso-propyl and benzyl;
Q C is selected from N and CH:
Y and Y′ are selected from O, S, or NH;
when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) C 6-10 carboaryl group or C 5-10 heteroaryl group, wherein said C 6-10 carboaryl or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 6-10 carboaryl or C 5-10 heteroaryl group;
(ib) C 1-5 alkyl;
(ic) C 3-6 cycloalkyl;
wherein each of R 11 , R 12 and R 13 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl:
when there is a single bond present between C2 and C3,
R 2 is H or
where R 16a and R 16b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 2′ is selected from the group consisting of:
(iia) C 6-10 carboaryl group or a C 5-10 heteroaryl group, wherein said C 6-10 carboaryl group or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 6-10 carboaryl or a C 5-10 heteroaryl group;
(iib) C 1-5 alkyl;
(iic) C 3-6 cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2′ group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy: pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 alkyl: C 2-3 alkenyl: C 2-3 alkynyl: cyclopropyl: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 2′ is H or
where R 26a and R 26b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester; R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from C 1-12 alkyl, C 3-20 heterocyclyl and C 6-20 aryl groups;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 11a is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
and either
(a) R 30 is H, and R 31 is OH, OR A , where R A is C 1-4 alkyl;
(b) R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 30 is H and R 31 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, wherein if R 11a and R 31 are SO z M, M may represent a divalent pharmaceutically acceptable cation;
R LL is a linker for connection to an antibody or an antigen-binding fragment of an antibody, which is selected from:
where Q is:
where Q X is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue;
X is:
where a=0 to 5, b=0 to 16, c=0 or 1, d=0 to 5; and
G LL is a linker connected to an antibody or an antigen-binding fragment of an antibody; and
where R L1 and R L2 are independently selected from H and methyl, or together with the carbon atom to which they are bound form a cyclopropylene or cyclobutylene group;
and e is 0 or 1;
wherein the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the heterocyclyl group in C 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; and
wherein the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein p is an integer of from 1 to 20.
10. A conjugate according to claim 9 , wherein G LL is selected from:
(G LL1-1 )
(G LL1-2 )
(G LL2 )
(G LL3-1 )
(G LL3-2 )
(G LL-4 )
(G LL5 )
(G LL6 )
(G LL7 )
(G LL8-1 )
(G LL8-2)
(G LL9-1)
(G LL9-2 )
G L10
G L11
G L12
G L13
where Ar represents phenylene and X represents C 1-4 alkyl.
11. A conjugate according to claim 9 , wherein D L is of:
(i) formula IIIa:
where R 2a and R 2a′ are the same and are selected from:
(ii) formula IIIb:
(iii) formula IIIc:
where R 7a and R 7a′ are the same and are selected from methoxy and benzyloxy.
12. The conjugate according to claim 9 , wherein the antibody or antibody fragment is an antibody which binds to one or more tumor-associated antigens or cell-surface receptors selected from (1)-(88):
(1) BMPR1B;
(2) E16;
(3) STEAP1;
(4) 0772P;
(5) MPF;
(6) Napi3b;
(7) Sema 5b;
(8) PSCA hlg;
(9) ETBR;
(10) MSG783;
(11) STEAP2;
(12) TrpM4;
(13) CRIPTO;
(14) CD21;
(15) CD79b;
(16) FcRH2;
(17) HER2;
(18) NCA;
(19) MDP;
(20) IL20R-alpha;
(21) Brevican;
(22) EphB2R;
(23) ASLG659;
(24) PSCA;
(25) GEDA;
(26) BAFF-R;
(27) CD22;
(28) CD79a;
(29) CXCR5;
(30) HLA-DOB;
(31) P2X5;
(32) CD72;
(33) LY64;
(34) FcRH1;
(35) IRTA2;
(36) TENB2;
(37) PSMA—FOLH1;
(38) SST;
(38.1) SSTR2;
(38.2) SSTR5;
(38.3) SSTR1;
(38.4) SSTR3;
(38.5) SSTR4;
(39) ITGAV;
(40) ITGB6;
(41) CEACAM5;
(42) MET;
(43) MUCI;
(44) CA9;
(45) EGFRvIII;
(46) CD33;
(47) CD19;
(48) IL2RA;
(49) AXL;
(50) CD30—TNFRSF8;
(51) BCMA—TNFRSF17;
(52) CT Ags—CTA;
(53) CD174 (Lewis Y)—FUT3;
(54) CLEC14A;
(55) GRP78—HSPA5;
(56) CD70;
(57) Stem Cell specific antigens;
(58) ASG-5;
(59) ENPP3;
(60) PRR4;
(61) GCC—GUCY2C;
(62) Liv-1—SLC39A6;
(63) 5T4;
(64) CD56—NCMA1;
(65) CanAg;
(66) FOLR1;
(67) GPNMB;
(68) TIM-1—HAVCR1;
(69) RG-1/Prostate tumor target Mindin—Mindin/RG-1;
(70) B7-H4—VTCN1;
(71) PTK7;
(72) CD37;
(73) CD138—SDC1;
(74) CD74;
(75) Claudins—CLs;
(76) EGFR;
(77) Her3;
(78) RON—MST1R;
(79) EPHA2;
(80) CD20—MS4A1;
(81) Tenascin C—TNC;
(82) FAP;
(83) DKK-1;
(84) CD52;
(85) CS1—SLAMF7;
(86) Endoglin—ENG;
(87) Annexin A1—ANXA1;
(88) V-CAM (CD106)—VCAM1.
13. A composition comprising a mixture of conjugates according to claim 9 , wherein the average p in the mixture of conjugate compounds is about 1 to about 8.
14. A pharmaceutical composition comprising the conjugate of claim 8 and a pharmaceutically acceptable diluent, carrier or excipient.
15. A method of treating a mammal having gastric carcinoma, gastrointestinal cancer or leukaemia, comprising administering an effective amount of a conjugate of claim 8 or a pharmaceutical composition of claim 14 .
16. A compound of formula REL:
or a pharmaceutically acceptable salt thereof, wherein:
R″ is a group of formula II:
where each of n and m are independently selected from 1, 2 and 3;
R O is selected from the group consisting of H, methyl, ethyl, iso-propyl and benzyl;
Q C is selected from N and CH,
Y and Y′ are selected from O, S, or NH;
when there is a double bond present between C2 and C3, R 2 is selected from the group consisting of:
(ia) C 6-10 carboaryl group or C 5-10 heteroaryl group, wherein said C 6-10 carboaryl group or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 6-10 carboaryl or a C 5-10 heteroaryl group;
(ib) C 1-5 alkyl;
(ic) C 3-6 cycloalkyl;
wherein each of R 11 , R 12 and R 13 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
wherein one of R 15a and R 15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 14 is selected from: H; C 1-3 alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2 and C3,
R 2 is H or
where R 16a and R 16b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
when there is a double bond present between C2′ and C3′, R 2′ is selected from the group consisting of:
(iia) C 6-10 carboaryl group or C 5-10 heteroaryl group, wherein said C 6-10 carboaryl group or C 5-10 heteroaryl group is optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, —OR, carboxy, —C(═O)OR, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene, wherein R is selected from a C 1-7 alkyl group, a C 3-20 heterocyclyl group or a C 6-10 carboaryl or a C 5-10 heteroaryl group;
(iib) C 1-5 alkyl;
(iic) C 3-6 cycloalkyl;
wherein each of R 21 , R 22 and R 23 are independently selected from H, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2′ group is no more than 5;
wherein one of R 25a and R 25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and
where R 24 is selected from: H; C 1-3 alkyl; C 2-3 alkenyl; C 2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl;
when there is a single bond present between C2′ and C3′,
R 2′ is H or
where R 26a and R 26b are independently selected from H, F, C 1-4 alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 26a and R 26b is H, the other is selected from nitrile and a C 1-4 alkyl ester; R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from C 1-12 alkyl, C 3-20 heterocyclyl and C 6-20 aryl groups;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NHRR′, nitro, Me 3 Sn and halo;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 respectively;
R 11a is selected from OH, OR A , where R A is C 1-4 alkyl, and SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
and either
(a) R 30 is H, and R 31 is OH, OR A , where R A is C 1-4 alkyl;
(b) R 30 and R 31 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 30 is H and R 31 is SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation, wherein if R 11a and R 31 are SO z M, M may represent a divalent pharmaceutically acceptable cation;
wherein the heterocyclyl group in C 3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S;
wherein the heterocyclyl group in C 3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; and
wherein the heteroaryl group in C 5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S.Join the waitlist — get patent alerts
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